Earlier this year, while COVID-19 was still a localized outbreak in China, Eleanor Fish, an immunologist at the University of Toronto, contacted Wuhan colleagues to explore the option of comparing interferon treatment in coronavirus-infected patients. Fish has been reading interferons (IFNs), proteins produced through the framework in reaction to viral infections, for approximately 35 years, and its past positive effects with an artificial edition of the SARS outbreak in Canada in 2003 motivated the idea.
Fish’s colleagues in China contacted Qiong Zhou, a doctor who was treating coVID-19 patients at Wuhan Union Hospital at the time. Zhou was very receptive to the proposal, Fish recalls. As it was an outbreak, there was no time to optimize an IFN for use as opposed to SARS-CoV-2, and Fish and Zhou had to settle for what was to be taken and what had already been effectively attempted in other coronavirus infections. For a clinical study, Zhou’s team used IFN-alpha-2b, first approved by the U.S. Food and Drug Administration (FDA) for cancer treatment in 1986, with its immunomodulatory, antiproliferative and antiangiogenic effects. Researchers tested IFN and arbidol, a widely used broad-spectrum antiviral drug, in 77 patients admitted to the EU hospital in January and February with a SARS-CoV-2 infection. Each had moderate symptoms and none required extensive care.
The results, published May 15 at Frontiers in Immunology, revealed that patients treated with IFN-alpha-2b or in mixture with arbidol removed the virus from their upper respiratory tract on average seven days faster than the organization receiving arbidolArray at the same time, blood The degrees of inflammatory markers such as interleukin-6 and C-reactive protein were particularly reduced in patients receiving IFN-alpha-2b. Fish adds that unregistred knowledge shows that IFN-alpha-2b also limited lung abnormalities, as evidenced by CT scans.
The general consensus on the ground is that any antiviral in COVID is used early, even as a preventive measure.
“I think it’s a decent clinical report, and they’re looking for inflammatory markers, which is important,” says Andreas Wack, an immunologist at the Francis Crick Institute in London who works at IFN but isn’t worried about the study. This is because IFN-alpha is known to induce a pro-inflammatory medium. Fish said that in his study, patients treated with IFN-alpha-2b showed no evidence of a cytokine storm, one of the harmful immune responses observed in some patients with COVID-19.
Jordan Feld, a hepatologist at Toronto General Hospital, says that while the test is not a randomized controlled trial, it does promise the concept of NFI in COVID-19. On 20 July, a British company called Synairgen reported on unreleased knowledge of a phase 2 trial of an ifN experimental drug, NEbulized IFN-beta, which gave the impression of reducing the threat of developing a serious illness by 79% in patients hospitalized with COVID -19.
Any new clues about drugs are welcome in this pandemic. Only the remdesivir antiviral agent has received an FDA emergency use authorization for the treatment of patients with severe COVID-19. On 25 June, the initial encouraging effects of the UK RECOVERY trial led the U.S. National Institutes of Health (NIH) to develop dexamethasone, a corticosteroid, for the treatment of COVID-19 patients undergoing mechanical ventilation or those requiring oxygen. But there are still no approved medications to administer at the beginning of infection or as a preventive measure for others at high risk.
In such a bleak therapeutic scenario, mounting evidence from laboratory studies and a couple of clinical trials on IFNs, either alone or in combination with other antivirals, suggests that synthetic IFNs might be able to fill in this gap.
There are three types of natural IFNs, each secreted by their own suite of cell types. Both type I (IFN-alpha and IFN-beta) and type III (IFN-lambda) are antiviral proteins produced early on in infected cells to protect other cells in the vicinity. “Once the genetic material [of the virus] is exposed, [IFNs] will chew it up,” says Fish. At the same time, IFNs recruit to the site of infection immune cells that will also help clear the virus.
IFNs I and III, for the most part, are part and parcel of the innate immune response of the body, with type III specifically involved in the localized immune response at sites where pathogens enter the body, such as mucosal barriers of the lungs, intestines, and liver. But the body’s natural IFN response doesn’t appear to be enough to thwart SARS-CoV-2 infection.
A paper published in Cell on May 28 by Benjamin tenOever, a virologist at the Icahn School of Medicine at Mount Sinai in New York, and colleagues found that SARS-CoV-2 infection induces low levels of type I and type III IFNs in ferrets. And Fish and Wack note that all viruses have numerous mechanisms to dampen the IFN response.
It stands to reason, therefore, that giving synthetic IFN drugs would boost the antiviral immunity of the body, perhaps giving the host the upper hand.
While IFN specialists posit that type I and III IFN drugs are attractive therapeutic options in COVID-19, they disagree about which of the two would be most suitable in COVID-19, and experimental evidence indicates that both types have potential.
A study published on June 19 shows that the in-beta-1a type, recently approved for the treatment of multiple sclerosis, was very effective in inhibiting replication of SARS-CoV-2 in vitro. A prepress published on May 7 shows that the remedy with clinical candidate IFN-lambda-1a, a type III IFN, inhibits replication of SARS-CoV-2 both in vitro and in mouse models. Another prepress published on 20 May shows that type I and type III NFI reduce SARS-CoV-2 replication in number one human airway epithelial cultures.
Although no artificial IFN-lambda has yet been approved through the FDA, the initial effects of a clinical trial in patients with hepatitis D show that it has the same antiviral potency as TYPE IN IFN but is much safer and more tolerated. A mouse test found that artificial IFN-lambda was as effective as IFN-alpha in the treatment of influenza, but it did not have the same pro-inflammatory effects.
The limited-looking effects of IFN-lambda may simply be due to the receptor distribution model, which appears exclusively on barrier surfaces, such as the epithelium of the lung, intestine and liver, while type I IN receptors are ubiquitous, Glenn explains. at Stanford University and founder of Eiger BioPharmaceuticals, a company that manufactures an IFN-lambda drug. “The benefit/risk ratio is compelling [for IFN-lambda]. IFN-alpha is a very difficult drug to take because it has many side effects. These come with flu-like symptoms, fatigue, low blood counts, insomnia and genius disorders. .
I’d be very, very, very much about it.
Ludmila Prokunina-Olsson, principal investigator of the NIH who discovered and cloned a new IFN-lambda gene in 2013 and is not related to any ifN clinical trial for COVID-19, told the scientist in an email that type I IFN is a very potent antiviral but its mode of action is more inflammatory. “There is enough inflammation in COVID lungs and it is essential for any additional inflammation,” she says. “If you use interferons, we recommend that you use IFN-lambda.”
Michael Gale Jr., an immunologist at the University of Washington who is recently working on how host cells recognize SARS-CoV-2 and trigger the innate immune reaction, but is not involved in IFN-lambda trials, also supports the clinical use of IFN-lambda. “With SARS-CoV-2, it’s not about activating the lymphocytes, as they are already activated in the inflammatory process.” Because IFN-lambda receptors are not expressed in lymphocytes, immune cells are not activated.
IFN-lambda trialists say they worry that type I IFN, which is known to be proinflammatory, could precipitate a cytokine storm in COVID-19 patients. A study published July 10 in Science Immunology confirms that the type I IFN response is indeed proinflammatory in coronavirus infections and plays a pivotal role in the development of severe COVID-19.
“I would be very hesitant to use type I IFN,” says Thomas Marron, a cancer immunologist at the Icahn School of Medicine at Mount Sinai who is leading an IFN-lambda trial.
But for many researchers, type I IFN is not off the table for treating COVID-19. While Feld, an IFN-lambda proponent, is likewise concerned about type I IFNs’ safety in this context, he says what is appealing about type I IFNs is that being approved drugs, they can be mass-produced and given right away. “Obviously, even if we prove that IFN-lambda is highly effective, getting it mass produced will be a challenge.” Additionally, advocates of type I IFN drugs posit that the concerns about IFN-alpha’s tolerability are not so much an issue with short-term treatment in an acute viral infection such as COVID-19. And as SARS-CoV-2 spreads systemically, IFN-lambda won’t protect all cell types.
IFN-lambda has another downside. If given for too long or at too high a dose, Gale cautions, “we could run into problems where it would impede tissue regeneration,” particularly in the lungs. In a study published in June, Wack’s team found that type I and III IFNs activate antiproliferative and cell death pathways in airway epithelial cells of mice infected with influenza virus and that excessive or prolonged IFN production disrupted lung epithelial repair during recovery from the viral infection.
Harvard Medical School’s Ivan Zanoni led a second study also published last month that generated similar results regarding IFN-lambda using a synthetic version of SARS-CoV-2. He tells The Scientist that IFNs might be very good when given early in COVID-19 to limit the spread of infection. “When you move to severe COVID-19, ICU patients or hospitalized patients, one has to very careful as we have found that [both type I and type III] IFNs have a dark side,” he says.
“The general consensus on the ground is that any antiviral contained in COVID is used early, even as a preventive measure,” says Prokunina-Olsson. “In the later stages of the disease, when the infection spreads to the lungs, any antiviral can be dangerous” due to the threat of a cytokine typhoon or damage to lung tissue through immune cells.
Both Wack and Zanoni emphasize to The Scientist the need to exercise caution with such potent antivirals as IFNs. “It’s complicated,” says Wack, “and I would be very, very, very cautious about this.”
Type I and III NFI are being tested lately in clinical trials around the world. In a randomized phase 2 multicenter trial in Hong Kong that was published in The Lancet on May 8, triple antiviral treatment with injectable IFN-beta-1b, lopinavir-ritonavir (an oral protease inhibitor) and ribavirin (an oral nucleoside analogue) was and incredible to lopinavir-ritonavir only to decrease the duration of virus excretion, minimize symptoms and allow patients with mild to moderate COVID-19 to return home sooner.
Synairgen’s ongoing randomized controlled trial in the UK is testing inhaled IFN-beta-1a instead of placebo in patients hospitalized with COVID-19 shown or suspected, unins hospitalized patients with chronic physical conditioning situations and front-line fitness personnel at the greatest threat to coronavirus infections. Evangelos Andreakos, an immunologist founded in Athens, Greece, says the use of type I IFN in inhalation is an attractive technique that can overcome the systemic effects of the drug by administering it directly to the lungs.
Other trials come with the WHO SOLIDARITY trial, presented on 20 March, which comes with the ifN-beta test along with other antiviral drugs, and an open trial in China, which reported on 7 May in a prepress that IFN-alpha nasal drops appeared. to save it from coronavirus infections in approximately 3,000 medical workers. In addition, Fish is an active partner for conducting ifN-alpha clinical trials in COVID-19 patients in India and elsewhere.
For Type III NFI, there are lately six clinical trials in Eiger BioPharmaceuticals IFN-lambda from the U.S. And Canada on a wide variety of patients with COVID-19.
Upinder Singh, a Specialist in Infectious Diseases at Stanford University who is conducting one of these ifN-lambda trials, says his exam focuses exclusively on outpatients of COVID-19. The explanation is why 80% of inflamed patients will never be admitted. “But they are the ones who spread it in the community. Our purpose is to identify patients who are at a very early stage of the disease, the concept is that if you can do it early, it can decrease viral loss and minimize quarantine time.” Says. So far, about 60 patients have been recruited in the Stanford trial.
A Marron trial is being conducted at Mount Sinai and another at Massachusetts General Hospital in Boston is testing Eiger’s IFN-lambda in patients inpatients with COVID-19, while one trial at Johns Hopkins University is testing preventive use of the drug in others at the greatest threat of infection meanwhile, the initial effects of a trial in inpatients and outpatients , Feld, shows that the drug has and has minimal side effects, told The Scientist.
Clifford Lane, Deputy Director of Clinical Research and Special Projects at the National Institute of Allergy and Infectious Diseases, highlights NIH remedy guidelines, which propose not to use type I IFN in COVID-19, unless in a clinical trial, the reason is that these NIF sometimes showed no advantages when used in patients with other coronavirus infections, and that the significant toxicities of type I IFN outweighed the potential benefits.
NiH rules also imply that of the two type I IFN, IFN-beta is more tolerated than IFN-alpha, however, the effects of a recent randomized controlled trial do not help the use of IFN-beta-1a in the remedy of acute respiratory diseases. misery syndrome
Pointing out the excitement surrounding the use of IFN-lambda in COVID-19, Lane says, “I am open to all new approaches whenever tested.”